MATR3 pathogenic variants differentially impair its cryptic splicing repression function

Area of Science:

• Molecular Biology
• Genetics
• Neuroscience

Background:

• Matrin-3 (MATR3) is an RNA-binding protein associated with neurodegenerative and neurodevelopmental diseases.
• The role of MATR3 in cryptic splicing within functional genes and the impact of disease variants remain largely unknown.

Purpose of the Study:

• To investigate the function of MATR3 in regulating cryptic splicing in functional genes.
• To determine how disease-associated MATR3 variants affect its RNA-binding, solubility, and splicing repression activities.

Main Methods:

• Analysis of cryptic exon inclusion upon MATR3 loss.
• Assessment of RNA binding and solubility for wild-type and variant MATR3 proteins.
• Evaluation of the impact of variants on MATR3's cryptic splicing repression function.

Main Results:

• Loss of MATR3 leads to widespread cryptic exon inclusion in various transcripts.
• The ALS-linked S85C variant reduces MATR3 solubility but preserves RNA binding.
• A novel neurodevelopmental disease variant, M548T, impairs MATR3 solubility, RNA binding, and cryptic splicing repression.

Conclusions:

• MATR3 plays a critical role in repressing cryptic splicing events within functional genes.
• Disease-associated MATR3 variants can disrupt its function through altered solubility and RNA binding, contributing to disease pathogenesis.